DESCRIPTION: A broad and comprehensive program focusing on the development and application of novel synthetic methodologies is described in this revised application. The investigations build on past efforts in which new and efficient methods for N-heterocycle synthesis have been uncovered. During the past grant period, studies conducted by the PI's research group have led to the development of a mild oxidative method for iminium and N-acyliminium cation generation. This methodology can be used to promote efficient, stereocontrolled Mannich cyclization processes which lead to sterocontrolled production of highly functionalized piperidines in non-racemic form. In continuing efforts, the preparative potential of this unique process will be fully explored and expanded. In addition, the novel methods developed will be applied to the synthesis of biomedically interesting amino sugar, hydroxylated indolizidine and pyrrolizidine alkaloids. The targets selected include deoxymannojirimimycin and other deoxy-amino sugars, the pyrrolizidine alkaloids trachelanthamidine, platynecine and retronecine, and castanospermine related indolizidine alkaloids. The second phase of the proposed program focuses on an interesting, yet underdeveloped, photoreaction of pyridinium salts. This photochemical process produces highly functionalized 4-aminocyclopentenes and is attended by high and potentially controllable degrees of stereo- and regio-chemical control. The first aim of future investigations in this area is to fully explore the preparative scope of the photochemical process in the context of developing its complete synthetic dexterity. The second aim of this work is to demonstrate the preparative power of this novel photochemical process through applications to the synthesis of functionally and stereochemically complex and biomedically important natural products. Included in the targets selected for this phase of the effort are the mannosidase inhibitor mannostatin, the sialic acid N-acetylneuraminic acid, the glycosidase inhibitor trehazolin and the novel gamma-lactam lactacystin.